This is a prospective, non-randomized clinical trial designed to study the biologic effects of combination biochemopreventive therapy for the reversal of advanced premalignant lesions including moderate and severe dysplasia in the upper aerodigestive tract. Chemopreventive therapy using retinoids alone has not been effective for the advanced premalignant lesions that will imminently develop into invasive cancer. Therefore, we propose a more aggressive regimen including 13-cis-retinoic acid (13cRA), alpha-tocopherol, and interferon-alpha for these advanced premalignant lesions. Biomarker studies have been incorporated to enhance understanding of pathophysiology for the tumor development and risk assessment, and as "intermediate endpoints" in the chemoprevention trial. The hypotheses underlying this proposal are: 1) advanced premalignant lesions in the epithelium of the upper aerodigestive tract result from chronic carcinogen exposure and may serve as a model for developing chemoprevention studies; 2) biomarkers may be used to define the molecular and cellular changes of field and multistep carcinogenesis, and to identify individuals at increased risk for the development of cancer; and 3) biochemopreventive therapy will be effective in reversing advanced premalignant lesions, and will modulate a panel of the expression of biomarkers. With these working hypotheses, we propose the following specific objectives: 1) to determine the efficacy and toxicity of biochemopreventive therapy in patients with advanced premalignant lesions; 2) to evaluate the effect of this combination in modulating the expression of biomarkers of carcinogenesis, including genetic markers (chromosomal changes, p53 expression/mutation), phenotypic changes (proliferating cell nuclear antigen, epidermal growth factor receptor), and nuclear retinoic acid receptors; and 3) to evaluate the measurement of cell apoptosis and interferon response as biological phenomenon of the effect of biochemopreventive therapy, including in situ end-labeling assay and interferon receptor analysis. To achieve these goals, all patients will receive interferon-alpha, 13cRA and alpha-tocopherol for 6 months, then will be evaluated for response. The responders will continue on therapy for 6 more months, and nonresponders will be taken offstudy and followed for up to 1 more year for all patients. Target sample size for this protocol will be 35 patients by the Simon's two- stage phase II trial. For the biomarker studies, we will utilize the paraffin-embedded biopsied specimens at baseline, 6 months, and 12 months of therapy. Using biopsied specimens, we will analyze genetic instability by chromosome in situ hybridization, p53 alterations by immunohistochemistry and PCR-SSCP/sequencing analysis, phenotypic alterations of PCNA and EGFR by immunohistochemistry, retinoic acid receptors by RNA in situ hybridization, and cell apoptosis and interferon response by in situ end labeling assay and interferon receptor analysis. This integration of biomarker studies into the chemoprevention trial will provide a unique opportunity to improve our pathobiological basis of understanding of tumorigenesis and responsiveness to the proposed therapy. This proposed translational research will eventually direct future intervention trials of premalignant lesions, not only in the upper aerodigestive tract, but also in other human epithelial malignancies.